1. Field of the Invention
This invention provides quinazoline compounds and pharmaceutically acceptable acid addition salts thereof having antihypertensive utility. In particular, the instant invention relates to novel 1,2,3-thiadiazole-carbonyl piperazinyl quinazolines which are potent and long acting antihypertensive drugs.
2. Description of the Prior Art
U.S. Pat. Nos. 3,511,836, 3,635,979, and 3,663,706 disclose various 4-amino-6,7-dimethoxy-2-[4-(heterocyclic-2-carbonyl)-piperazin-1-yl]-quina zolines. One of these compounds, i.e., 2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline described in Example LXXII of these patents is a clinically useful antihypertensive agent and is marketed as such in many countries of the world under the generic name prazosin. It is considered that the antihypertensive efficacy of prazosin results from a dual mechanism of action: (i) a direct peripheral vasodilation effect on vascular smooth muscle, and (ii) a functional peripheral .alpha.-adrenergic receptor blockade, H. Adriaensen, The Practitioner, 214, 268 (1975); Mroczek, et al., Current Therapeutic Research, 16, 769 (1974); Scriabine, et al., Experimentia, 24, 1150 (1968); Constantine, et al., "Hypertension: Mechanisms and Management", ed. by Onesti, Kim and Moyer; Grune and Stratton, 1973 pp. 429-44; and Zacest, Med. J. of Austral. Special Supplement, 1, 4 (1975). Although initial clinical assessments on prazosin indicated a low incidence of side effects, recent reports have revealed severe adverse reactions of postural hypotension in some patients, Bendall, et al., Brit. Med. J., 727 (June 29, 1975); Rees, Brit. Med. J., 593 (Sept. 6, 1975); Gabriel, et al., The Lancet, 1095 (May 10, 1975); and Bloom, et al., Current Therapeutic Research, 18, 144 (1975). It is believed that this type of side effect results from the .alpha.-blockade component of prazosin. Indeed, it has been stated by R. Zacest in the Med. J. of Austral., Special Supplement, 1, 4 (1975) that "if the alpha adrenergic `blocking` activity does prove to be significant with high doses it may lead to postural hypotension".
U.S. Pat. Nos. 3,669,968 and 3,769,286 cover trialkoxyquinazolines, such as those having the formula ##STR1## wherein R may be a number of different groups including furyl and thienyl. These patents claim to have certain advantages over the corresponding 6,7-dialkoxy compounds such as those disclosed in the patents previously discussed. Thus, it is stated that such compounds "have a more favorable pharmacological profile (e.g., they are non-adrenolytic in dogs) and possess greatly improved solubility characteristics (particularly in water) as contrasted to the corresponding 6,7-dialkoxy compounds reported in the prior art". One of the compounds disclosed in these patents is known by the generic name trimazosin and has the formula ##STR2## Trimazosin is reported to be active in humans as an antihypertensive agent, DeGuia, et al., Current Therapeutic Research, 15, 339 (1973); Vlachakis, et al., Current Therapeutic Research, 17, 564 (1975). However, it is a much weaker drug than prazosin, the respective clinical daily dose ranges being approximately 150 to 500 mg. for trimazosin as compared to 1.5 to 15 mg. for prazosin.
U.S. Pat. Nos. 3,517,005, 3,594,480, and 3,812,127 describe certain piperazinyl quinazolines having both bronchodilator and antihypertensive activity, e.g., a compound having the formula ##STR3## wherein A and B may each be alkoxy, etc., R.sup.1 may be hydrogen or alkyl and R.sup.2 may be hydrogen or a radical such as alkyl, benzoyl, etc.
U.S. Pat. No. 3,920,636 describes homopiperazino quinazolines as antihypertensive agents, e.g., the compound ##STR4##
U.S. Pat. No. 4,001,238 discloses 1,2,4-oxadiazole amides useful as antihypertensive agents characterized by the formula ##STR5## in which R is (lower)alkyl.
U.S. Pat. No. 4,001,237 describes compounds having antihypertensive utility characterized by the formula ##STR6## wherein Z is an oxazole, isoxazole, thiazole and isothiazole radical.
U.S. Pat. No. 3,780,040 discloses compounds useful as antihypertensive agents such as the compound ##STR7##
Netherlands application No. 72 06,067 (CA, 78, 72180s) describes a process for preparing aminoquinazolines, such as prazosin, by treating the corresponding o-aminobenzonitrile in the presence of phenyl lithium according to the following mechanism ##STR8## wherein R.sub.2 N may be the group 4-(2-furoyl)-1-piperazinyl.